Human genetics has played a central role in the study of frontotemporal lobar dementia(FTLD). Identification of families with hereditary forms of FTLD has helped to validate clinical concepts and allowed for identification of tau gene mutations. The recognition that tau mutations can cause neurodegenerative disease has started a renaissance in tau biology research, and fostered the conclusion that tau plays a central role in neurodegeneration. Tau mutations can produce a broad spectrum of neurodegenerative disorders. Most patients with diseases in the spectrum caused by tau mutations do not have tau coding sequence mutations or known regulatory element mutations. It has become clear that mutations in other genes can lead to diseases similar to those seen with tau mutations. We propose to positionally clone a gene on chromosome 15 that causes FTLD with amyotrophy. Identification of this gene will lead to a greater understanding of the spectrum of diseases in which tau is implicated. Based on observations by many investigators, and preliminary data described in this proposal, there is more to learn about tau gene regulation and biology. We propose to identify new DNA sequence changes that affect susceptibility to sporadic FTLD and progressive supranuclear palsy. FTLD is more heritable than most of the neurodegenerative disorders, with 30-50% of cases having a family history of disease. We propose to determine where the major vulnerability factors are for this increased susceptibility, if they are not due to changes near the tau locus. The identification of mutations that predispose to disease offers an important opportunity to make phenotype-genotype correlations and learn about the natural history of FTLD with the hope that this insight will lead to effective therapies.